Original Study| Volume 15, ISSUE 6, P742-749, December 2017

A Phase II Trial of AEZS-108 in Castration- and Taxane-Resistant Prostate Cancer



      AEZS-108 (zoptarelin doxorubicin) is a cytotoxic hybrid molecule consisting of doxorubicin covalently coupled with a luteinizing hormone-releasing hormone (LHRH) analogue, which selectively targets doxorubicin to tumor cells expressing LHRH receptors. We report the clinical efficacy of AEZS-108 in a phase II trial in men with metastatic castrate-resistant prostate cancer who had disease progression after taxane-based chemotherapy.

      Patients and Methods

      Patients received AEZS-108 210 mg/m2 intravenously every 3 weeks. The primary end point was clinical benefit defined as nonprogression at 12 weeks with no dose-limiting toxicities (DLTs) or other toxicities requiring termination of treatment. Secondary end points included response rate, pain response, progression-free survival (PFS), and overall survival (OS). Circulating tumor cells (CTCs) were captured and tested for LHRH receptors, as well as for internalization of AEZS-108 using autofluorescence.


      Twenty-five patients were enrolled; 20 patients had at least 1 measurable lesion at baseline. Patients received a median of 5 cycles (range, 1-9) and 44% of patients received at least 6 cycles with 2 patients who completed ≥ 8 cycles. Considering clinical benefits, 13 patients (52%) remained progression-free at 12 weeks with no DLT or other toxicities requiring termination of treatment. For clinical response according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, 1 patient (4%) experienced a confirmed partial response (PR) within 12 weeks, 14 patients (56%) had stable disease (SD), and 8 patients (32%) had disease progression. For maximal prostate-specific antigen (PSA) response, 1 patient (4%) experienced a confirmed PR within 12 weeks, 21 patients (84%) had SD, and 3 patients (12%) had disease progression as denoted by their best PSA response. Pain improved in 13 (59%) patients. The median PFS was 3.8 months (95% confidence interval [CI], 2.1-4.4), and median OS was 6.0 months (95% CI, 4.2-10.1) with a median follow-up of 16.1 months (range, 3.2-36.1). Baseline CTC enumeration was an independent predictor of OS but not PFS.


      AEZS-108 showed activity in patients who were pretreated, a subset typically very difficult to treat, and maintained an acceptable safety profile.


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        • Sweeney C.
        • Chen Y.
        • Carducci M.
        • et al.
        Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.
        N Engl J Med. 2015; 373: 737-774
        • Basch E.M.
        • Somerfield M.R.
        • Beer T.M.
        • et al.
        American Society of Clinical Oncology endorsement of the Cancer Care Ontario Practice Guideline on nonhormonal therapy for men with metastatic hormone-refractory (castration-resistant) prostate cancer.
        J Clin Oncol. 2007; 25: 5313
        • Tannock I.F.
        • de Wit R.
        • Berry W.R.
        • et al.
        Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
        N Engl J Med. 2004; 351: 1502-1512
        • Petrylak D.
        • Tangen C.M.
        • Hussain M.
        • et al.
        Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.
        N Engl J Med. 2004; 351: 1513-1520
        • Liang X.J.
        • Chen C.
        • Zhao Y.
        • Wang P.C.
        Circumventing tumor resistance to chemotherapy by nanotechnology.
        Methods Mol Biol. 2010; 596: 467-488
        • Scher H.I.
        • Halabi S.
        • Tannock I.
        Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
        J Clin Oncol. 2008; 26: 1148-1159
        • Heidenreich A.
        • Bastian P.J.
        • Bellmunt J.
        • et al.
        EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer.
        Eur Urol. 2014; 65: 467-479
        • Gerber D.
        Targeted therapies: a new generation of cancer treatments.
        Am Fam Physician. 2008; 77: 311-319
        • Letsch M.
        • Schally A.V.
        • Szepeshazi K.
        • Halmos G.
        • Nagy A.
        Preclinical evaluation of targeted cytotoxic luteinizing hormone-releasing hormone analogue AN-152 in androgen-sensitive and insensitive prostate cancers.
        Clin Cancer Res. 2003; 9: 4505-4513
        • Popovics P.
        • Schally A.V.
        • Szalontay L.
        • Block N.L.
        • Rick F.G.
        Targeted cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AEZS-108 (AN-152), inhibits the growth of DU-145 human castration-resistant prostate cancer in vivo and in vitro through elevating P21 and ROS levels.
        Oncotarget. 2014; 5: 4567-4578
        • Halmos G.
        • Arencibia J.M.
        • Schally A.V.
        • Davis R.
        • Bostwick D.G.
        High incidence of receptors for luteinizing hormone-releasing hormone (LHRH) and LHRH receptor gene expression in human prostate cancers.
        J Urol. 2000; 163: 623-629
        • Liu S.V.
        • Schally A.V.
        • Hawes D.
        • et al.
        Expression of receptors for luteinizing hormone-releasing hormone (LHRH) in prostate cancers following therapy with LHRH agonists.
        Clin Cancer Res. 2010; 16: 4675-4680
        • Schally A.V.
        • Nagy A.
        Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors.
        Eur J Endocrinol. 1999; 141: 1-14
        • Schally A.V.
        • Nagy A.
        New approaches to treatment of various cancers based on cytotoxic analogs of LHRH, somatostatin and bombesin.
        Life Sci. 2003; 72: 2305-2320
        • Nagy A.
        • Schally A.V.
        Targeting cytotoxic conjugates of somatostatin, luteinizing hormone-releasing hormone and bombesin to cancers expressing their receptors: a smarter chemotherapy.
        Curr Pharm Des. 2005; 11: 1167-1180
        • Gunthert A.R.
        • Gründker C.
        • Bongertz T.
        • et al.
        Internalization of cytotoxic analog AN-152 of luteinizing hormone-releasing hormone induces apoptosis in human endometrial and ovarian cancer cell lines independent of multidrug resistance-1 (MDR-1) system.
        Am J Obstet Gynecol. 2004; 191: 1164-1172
        • Emons G.
        • Kaufmann M.
        • Gorchev G.
        • et al.
        Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors.
        Gynecol Oncol. 2010; 119: 457-461
        • Buchholz S.
        • Engel J.
        • Schally A.V.
        • et al.
        A randomized, phase II trial of AEZS-108 in chemotherapy refractory triple-negative (ER/PR/HER2-negative) LHRH-R positive metastatic breast cancer.
        J Clin Oncol. 2013; 31 (abstract TPS11124)
        • Emons G.
        • Gorchev G.
        • Harter P.
        • et al.
        Efficacy and safety of AEZS-108 (LHRH agonist linked to doxorubicin) in women with advanced or recurrent endometrial cancer expressing LHRH receptors: a multicenter phase 2 trial (AGO-GYN5).
        Int J Gynecol Cancer. 2014; 24: 260-265
        • Liu S.V.
        • Tsao-Wei D.D.
        • Shigang X.
        • et al.
        Phase I, dose-escalation study of the targeted cytotoxic LHRH analog AEZS-108 in patients with castration- and taxane-resistant prostate cancer.
        Clin Cancer Res. 2014; 20: 6277-6283
        • Arlen P.M.
        • Bianco F.
        • Dahut W.L.
        • et al.
        Prostate-Specific Antigen Working Group guidelines on prostate-specific antigen doubling time.
        J Urol. 2008; 179: 2181-2185
      1. US FDA. FDA approval document Nr K050245. 2005. Available at:

        • Scher H.I.
        • Fizazi K.
        • Saad F.
        • et al.
        Increased survival with enzalutamide in prostate cancer after chemotherapy.
        N Engl J Med. 2012; 367: 1187
        • de Bono J.S.
        • Logothetis C.J.
        • Molina A.
        • et al.
        Abiraterone and increased survival in metastatic prostate cancer.
        N Engl J Med. 2011; 364: 1995-2005
        • de Bono J.S.
        • Oudard S.
        • Ozguroglu M.
        • et al.
        Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.
        Lancet. 2010; 376: 1147-1154
        • de Bono J.S.
        • Scher H.I.
        • Montgomery B.R.
        • et al.
        Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.
        Clin Cancer Res. 2008; 14: 6302-6309
        • Danila D.C.
        • Heller G.
        • Gignac G.A.
        • et al.
        Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer.
        Clin Cancer Res. 2007; 13: 7053-7058
        • Ontenk W.
        • de Klaver W.
        • de Wit R.
        • Lolkema M.
        • Foekens J.
        • Sleijfer S.
        The use of circulating tumor cells in guiding treatment decisions for patients with metastatic castration-resistant prostate cancer.
        Cancer Treat Rev. 2016; 46: 42-50